The present invention relates to a method for determining the dissolution rate of small particles and more particularly relates to determining the dissolution rate of small particles by way of light scattering methods.
High bioavailability and short dissolution times are desirable attributes of a pharmaceutical end product. Bioavailability is a term meaning the degree to which a pharmaceutical product, or drug, becomes available to the target tissue after being administered to the body. Poor bioavailability is a significant problem encountered in the development of pharmaceutical compositions, particularly those containing an active ingredient that is poorly soluble in water. Poorly water soluble drugs tend to be eliminated from the gastrointestinal tract before being absorbed into the circulation.
Dissolution time is one indication of bioavailability. Dissolution time is defined as the time it takes for a certain amount of material to dissolve in a liquid. Dissolution time is typically measured by first adding the drug substance to a dissolution media, then sampling that media at various times, filtering to remove undissolved materials, followed by HPLC analysis of the filtrate to determine the amount of dissolved drug. However, these methods measure static dissolution and are not suitable for measuring the dynamic, or real time dissolution of a material. HPLC methods are also relatively time consuming and inefficient. Moreover, HPLC methods provide very little discernment of enhancements in dissolution rates.
One method that can be used to measure dynamic dissolution is ultraviolet (UV) measurement. However, UV methods are only useful when the molecule being measured absorbs light in the UV region. In addition, UV methods are limited by the particle size of the molecule being measured. As the size of the particles being measured approaches the wavelength of the light source, scattering interferes, so measurement of absorption becomes impossible because the scattering of the wavelength of light in question interferes with the measurement. In addition, UV methods provide very little discernment of enhancements in dissolution rates for small particles.
An alternative method to measure dissolution is turbidity, which is typically a value indicating the quantity of particles suspended in a liquid. Turbidity gives a quantitative measurement of the change of intensity of light passing through the medium, caused by absorptive interactions resulting in energy transfer to the medium and by scattering from optical inhomogeneities in the medium. xe2x80x9cAbsorbancexe2x80x9d is also a term that is used interchangeably with turbidity.
In xe2x80x9cExperimental and computational approaches to estimate solubility and permeability in drug discovery and development settings, C. A. Lipinski et al., Advanced Drug Delivery Reviews 46 (2001), 3-26., turbidity has been used to predict the solubility of a drug. In Farinato and Rowell, Encyclopedia of Emulsion Technology, Vol. 1 pp. 444-451 (1983), turbidity is described as being useful for determining particle size for relatively large particles. However, these references refer only to xe2x80x9csnapshotxe2x80x9d, static quantities of dissolved material and do not describe the use of turbidity to measure dynamic dissolution times. Moreover, these references do not describe measuring particle sizes for small particles in addition to measuring dissolution rates.
It would be an advantage to provide an alternative method for determining dissolution time which could be used to detect dynamic dissolution time, which could be used to detect the size of small particles, and which could be used quickly and efficiently. It would also be an advantage to provide a simple technique that can be used in a variety of environments and at a variety of scales, either large or small.
In one aspect, the present invention is a method for determining the percent of a solid material dissolved into a liquid medium comprising combining the solid material and the liquid medium; determining the initial solid concentration (i); determining the dynamic solid concentration (d) using a light scattering technique; and calculating the percent dissolved material according to the formula: [(ixe2x88x92d)/i]xc3x97100.
In a second aspect, the present invention is a method for determining the dissolution rate of a solid material dissolved into a liquid medium comprising combining the solid material and the liquid medium; determining the initial solid concentration (i); waiting for a period of time (T); determining the dynamic solid concentration (d) using a light scattering technique; and calculating the dissolution rate of the solid material according to the formula: (ixe2x88x92d)/T.
In a third aspect, the present invention is a method for determining the particle size of a drug substance dispersed in a liquid medium, wherein the concentration of the solid material in the liquid medium is known, comprising measuring the turbidity of the dispersion; and calculating the particle size of the drug substance from the turbidity measurement.
The present invention enables the determination of percent dissolved material on a dynamic basis. The present invention also enables a better scrutiny of changes in percent dissolved material than the methods used previously. The present invention also provides a simple method to measure dissolution at a variety of scales, including at a very large commercial scale or at a very small miniaturized scale.